Gelatinous Sting

Review of: J. Prentis, P., Pavasovic, A., & S Norton, R. (2018). Sea Anemones: Quiet Achievers in the Field of Peptide Toxins. Toxins, 10(1), 36. DOI:10.3390/toxins10010036

If you search the VenomZone website under the cnidarian section, you will find that most cnidarian toxins are derived from sea anemones (Class Anthozoa, order Actiniaria). My first literature review is a paper about these “quiet achievers,” and the contribution their venoms have made to the study of peptides and proteins thanks to the advances in ‘omics technologies (transcriptomics, genomics, proteomics). All of this despite being less well studied compared to snakes, scorpions, and cone snails in the search for venom-derived drugs.

Specifically, this paper emphasizes the therapeutic potential of sea anemones by the presence of ShK. ShK is a peptide derivative from Stichodactyla helianthus that blocks potassium channels. Currently a peptide derivative, ShK-186, also known as Dalazatide, is in Phase II clinical trials for autoimmune treatments. There have been many additional sea anemone derived peptides explored for medical use: sodium channel toxins, probes on voltage gated-sodium channels, sodium channel blockers and channel mediators. You may notice that all of these toxins are involved in the manipulation of channels within the body. This is because sea anemone venoms are rich in neurotoxins, which target nervous system channels. These kinds of toxins would be ideal for treating pain and modulating anti-cancer neural networks.  However, many of these listed potential therapeutics lack the high specificity needed in a new drug. Continued research to determine novel peptide scaffolds, or means in which to form these peptides, is critical in finding new therapeutic options. And for clarities sake, it is possible to synthesize these proteins in the lab and test new scaffold artificially, but it is extremely expensive, the yield is poor, and often these artificial drugs do not work as well as natural products. In fact, it is likely almost half of current drugs on the market are derived from natural products, or chemicals found in nature. Why not let evolution do some of the work for us?

ShK targets the Kv 1.3 channel, used by a subset of white blood cells called effector T cells.  These effector T cells are modulators of autoimmune disease, so blocking these specific Kv 1.3 channels consequently blocks these cells. It makes these channel-specific toxins highly attractive targets for treating autoimmune disease. During the same time ShK was introduced as a potential new therapeutic drug, similar Kv 1.3 blockers from scorpions were also being tested but failed in their specificity. ShK had a high affinity for Kv 1.3, but also for three addition potassium channels. After producing several analogues of this peptide, ShK-186 showed “100-fold improvement” (p. 5) in selectivity from the other potassium channels. Currently, ShK-186 is being tested for lupus, multiple sclerosis, psoriasis, arthritis, and a variety of other autoimmune diseases.

What is particularly striking about the ShK scaffold is that it is not unique to sea anemones.  ShKT (ShK toxins) have shown to be considerably prevalent in anemone transciptomes and genomes, but are also found in other cnidarians and even other venomous animals. In fact, “at the time of [this article], the SMART database includes 3345 ShKT domains spread across 1797 proteins” (p.7). These ShK-containing proteins are found amongst animals, plants, fungi, even viruses. While this may be a stark amount of biodiversity for this particular toxins, it is also not totally surprising. This is a protein domain, which means it is a specific kind of structure that gets repeated, not necessarily the full primary structure (meaning the actual sequence composition). For instance, the native 35-residue ShK peptide introduced into clinical trials has a unique primary sequence compared to the scorpion venoms that were also introduced for the same purpose, blocking Kv 1.3 channels, as well as different disulfide bonding and tertiary structure (folding pattern). But the presence of two key peptide residues, Lys22 (Lyesine at position 22) and Tyr23 (Tyrosine at position 23) were the same between the scorpion and anemones toxin genes. Using the wide array of omics’ technologies available, we will be able to look at these ShKT’s across the animal kingdom. This is excited both for evolutionary biologists trying to understand the mechanisms driving the diversity of expression within this protein, and for pharmaceutical chemists trying to discover new drugs.

Let’s return to the anemones again and what ShK means for them. From a biological standpoint, ShKTs expression across various tissues of anemones may be just as interested as the presence of several different forms within the same animal. This differential expression may be directly correlated with different nematocytes types. The characteristic trait of all Cnidaria, nematocytes, are found all over sea anemones, but the type of nematocytes varies between tissues. For instance, sea anemones have specialized tentacles along the edge of the anemone called acrorhagi, which are specifically used for inter-species competition. Within the species Actinia tenebrosa, the nematocytes structures within acrorhagi are basitrichs and holotrichs, as opposed to basitrichs and spirocysts in the tentacles used for prey capture and defense, or just basitrichs in the mesenteric filaments (digestion). So what about the venom contents? Are these also differentially expressed, and how well correlated is that venom expression between cell type or tissue type? Answering these kinds of questions would give us not only a better understanding of the organismal biology, but a better foundation in looking for relevant peptides for drug discovery.

The first paragraph from the Peptide Toxins from Anemones section (Section 3) makes several key points, in fact one that relates to the first sentence in this post. At the time of this article, there were 236 toxins in the ToxProt database that were from 45 sea anemones, 45 species out of 1100. Of those 236, 206 were from the superfamily Actinioidea. This is an extreme case of sampling bias, which the authors are quick to point out. The authors also make a point that “there is every reason for optimism that the remaining 96% of species…will provide interesting new peptides, some of which will no doubt have therapeutic potential” (p. 4).

But I will remind you that those 236 toxins are representative of 263 TOTAL for all of Cnidaria. That is 89.7% of currently annotated cnidarian toxins and venoms that are solely coming from anemones.  As someone focused on Medusozoans (Scyphozoa, Cubozoa, Hydrozoa, and Staurozoa), which are upwards of 3,500 species, a personal goal of mine is to see the number of toxins between these major Cnidarian classes balanced out. It will be both a benefit to understanding the ecology and evolution of venoms within this group, and be beneficial in the search for novel venom-derived therapies.